OBJECTIVE This trial is an experimental approach to the possible causes of continence and voiding problems after urethra sparing radical cystectomy and orthotopic bladder substitution in women. METHODS Between January 1996 and January 1999 we included 24 mongrel female dogs in this 4-phase study of 6 dogs each. The effects of autonomic denervation of the urethra (phase 1) and urethral transection just distal to the bladder neck (phase 2) on the urethral pressure profile were recorded. In phase 3 the effects of autonomic denervation, urethral transection and pharmacological manipulation of the denervated transected urethra on the urethral pressure profile were studied in succession. In phase 4 the effects of pudendal nerve transection and pharmacological blockade were recorded. In the 12 phases 2 and 3 dogs the transected urethra was re-anastomosed to the bladder neck. Acute experiments were repeated after 2 and 6 months, urethrocystoscopy was done and post-void residual urine was estimated. Two of the latter dogs were sacrificed 6 months after the acute experiment and the urethras were histopathologically examined. RESULTS Autonomic denervation resulted in a 46% to 48% decrease in mean maximal pressure in the proximal urethra in phases 1 and 3 (p <0.001) with no significant effect on the distal urethra. Urethral transection in phase 2 did not affect the urethral pressure profile. Phentolamine injection after urethral denervation and transection in phase 3 produced a further reduction of 11.3% and 46.3% in mean resting pressure in the proximal and distal urethra, respectively, while succinyl choline produced a 38.1% further decrease in the distal urethra. Unilateral and bilateral pudendal denervation reduced pressure in the distal urethra significantly but not in the proximal urethra. When phentolamine was given thereafter, a further decrease of 38% and 2.4% resulted in resting pressure values in the proximal and distal urethra, respectively. The change in distal urethral pressure was marginally significant after succinyl choline injection (p = 0.05). Results were reproducible after 2 and 6 months. The proximal urethra remained patent with no post-void residual urine after autonomic denervation. There was no significant urethral fibrosis after realignment of the transected urethra in the 2 sacrificed phases 2 and 3 dogs. CONCLUSIONS From this study we concluded that autonomic denervation reduced pressure in the proximal urethra by less than 50%. Continuity of the urethra with the bladder is not necessary for proper urethral function. After autonomic denervation the proximal urethra remained patent with no subsequent fibrosis. In addition, no post-void residual urine was noted. Bilateral pudendal denervation did not completely block activity of the distal urethra. The nonneuromuscular components had a small role in the creation of urethral closure function.